BRPI1104014A2 - COMPOSITION AND METHODS FOR TREATMENT OF MYELODISPLASTIC SYNDROME - Google Patents

Abstract

COMPOSITIONS AND METHODS FOR TREATING MYELODYSPLASTIC SYNDROME. The present invention relates in general to compositions and methods for treating myelodysplastic syndrome. In one embodiment, this invention relates to methods for treating myelodysplastic syndrome with ezatiostat or a salt thereof and lenalidomide

Description

Patent Descriptive Report for "COMPOSITIONS AND METHODS FOR TREATMENT OF MYELODYSPLATIC SYNDROME".

Field of the Invention

The present invention relates to compositions and methods for

treatment of myelodysplastic syndrome.

State of the Art

Myelodysplastic Syndrome (s) (MDS) refers to a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis (blood cell production) involving one or more cell lines ( red blood cells, white blood cells or platelets) and a variable risk of transformation to acute myeloid leukemia (AML). This syndrome becomes more common with age. It is estimated that MDS affects approximately 300,000 people worldwide, 15 worldwide. According to the American Cancer Society, 10,000 to 20,000 new cases of MDS are diagnosed each year in the United States alone. Survival rates using current therapy range from 6 months to 6 years with patients who often require blood transfusions to administer their disease.

There are currently three drugs approved for the treatment of

MDS by the U.S. Food and Drug Administration (FDA). Lenalidomide is indicated for the treatment of transfusion-dependent MDS patients with del (5q) and lower-risk disease while azacitidine and decitabine are approved for all categories. With the exception of del (5q) patients, the response rate is approximately 50%, highlighting the need for clinical testing of new agents.

Ezatiostat and its salts are described in U.S. Patent No. 5,763,570. Ezatiostat has the chemical name IUPAC of ethyl (2S) -2-amino-5 - [[(2R) -3-benzylsulfanyl-1 - [[(1R) -2-ethoxy-2-oxo-1-phenylethyl] amino] -1-oxopropan-2-30 yl] amino] -5-oxopentanoate.

An example of an ezatiostat salt is the hydrochloride salt, ezatiostat hydrochloride (USAN), which has the molecular weight of 566.1, trademark of Telintra®, and CAS registration number 286942-97-0. U.S. Patent Application No. 13 / 041,136, filed March 4, 2011, describes a solvate and ezatiostat hydrochloride polymorphs.

Ezatiostat hydrochloride was evaluated for the treatment of 5 MDS in a Phase I-Ila study using a liposomal formulation (U.S. Patent No. 7,029,695) as reported in the 2005 Annual Meeting of the American Society for Hematology (Abstract # 2250) and by Raza et al. in Journal of Hematology & Oncology 2:20 (published May 13, 2009); and in a Phase I study using a tablet formulation, as reported in the 2007 Annual Meeting of the American Society for Hematology (Abstract # 1454) and by Raza et al., in Blood, 113: 6533-6540 (pre- published on April 27, 2009), and in a single patient case report by Quddus et al., in Journal of Hematology & Cancer, 3:16 (published April 23, 2010). ).

, 15 Full descriptions of each of the patents, applications for

The patent and publications referred to in this patent application are incorporated into this patent application by reference.

Summary of the Invention

In one embodiment, this invention is a method of treating MDS in a patient in which the patient has prior exposure to ialalide that the method comprises treating said patient with ezatostatate or a pharmaceutically acceptable salt thereof.

In one embodiment, this invention is a method of treating MDS by administering ezatiostat or a salt thereof and Ienalidomide.

In another embodiment, this invention is a method of treating MDS by administering ezatiostat or a salt thereof and ienalidomide followed by administering ezatiostat or a salt thereof alone.

In some embodiments, ezatiostat or a salt thereof is administered daily for at least 2 weeks. In some modalities, ezatiostat or a salt thereof is administered daily for at least 3 weeks. In the methods of this invention, ezatiostat or a salt thereof may be administered by a dosage regimen described in US Patent Application No. 13 / 108,752, entitled "COMPOSITIONS AND METHODS FOR TRADING MYELODYSPLASIC SYNDROME", filed May 5, 16, 2011, which is incorporated by reference in its entirety and claims priority over U.S. Provisional Application No. 61 / 352,371, filed June 7, 2010. For example, ezatiostat or a salt thereof may be administered in 2 gram cycles / day orally for 3 weeks a week, or 3 gram / day cycles orally for 2 10 weeks a week. Equivalent doses of ezatiostat for ezatostat itself or other ezatiostat salts or other routes of administration may also be used.

In yet another aspect, this invention provides use of ezatiostat or a salt thereof for the preparation of a medicament for treating a myelodysplastic syndrome in a patient who has had previous exposure to lenalidomide.

In yet another aspect, this invention provides use of ezatiostat or a salt thereof for the preparation of a medicament for treating a myelodysplastic syndrome in a patient, wherein ezatiostat or a salt thereof is administered with lenalidomide.

In another aspect, this invention provides a composition comprising lenalidomide and ezatiostat or a salt thereof. Such compositions preferably contain a pharmaceutically acceptable excipient for ease of administration.

In yet another aspect, this invention provides a set for

treating MDS comprising a first composition comprising lenalidomide and a second composition comprising ezatiostat or a salt thereof.

These and other embodiments of this invention are further described in the following text.

Detailed Description of the Invention

Prior to the description of this invention in more detail, the following terms will be first defined.

It should be understood that this invention is not limited to the particular embodiments described, as such, of course, may vary. It is also to be understood that the terminology used in this application is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

It should be noted that as used in this application and in the appended claims, the singular forms "one", "one" and "o" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutically acceptable excipient" includes a plurality of pharmaceutically acceptable excipients.

1. Definitions

.15 Unless otherwise defined, all technical terms

The scientific and scientific concepts used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used in this order, the following terms have the following meanings.

The term "comprising" or "comprising" means that the

compositions and methods include elements cited, but do not exclude others. "Consisting essentially in" when used to define compositions and methods shall mean excluding other elements of any essential significance for the purpose-matched combination. Accordingly, a composition consisting essentially of the elements as defined in this application would not exclude other materials or steps that do not materially affect the basic and novel feature (s) of the claimed invention. . "Consisting of" means excluding more than trace elements from other ingredients and substantial method steps. Modalities defined by each of these transition terms are within the scope of this invention.

The term "approximately" when used before a numerical designation, for example, temperature, time, amount and concentration, including range, indicates approximations which may vary by (+) or (-) 15%, 10%, 5% or 1%.

"Lenalidomide" (Revlimid®, also known as Revamid in the United Kingdom) is an immunomodulatory agent with antiangiogenic and antineoplastic properties. It has the chemical name 3- (4-amino-1-oxoisoindolin-2-yl) piperidin-2,6-dione or 1-oxo-2- (2,6-dioxopiperidin-3-yl) -4-aminoisoindrone. Iine or 3- (7-amino-3-oxo-1H-isoindol-2-yl) piperidine-2,6-dione, and CAS Registry Number 191732-72-6. Lenalidomide is indicated for the treatment of 10 patients who are transfusion dependent due to low or intermediate risk 1 MDS associated with a 5q deletion cytogenetic abnormality. Lenalidomide is available in capsules of 5 milligrams (mg), 10 mg, 15 mg and 25 mg for oral administration.

The term "therapeutically effective amount" refers to the amount of lenalidomide or the amount of ezatiostat or a salt thereof, or combination ("together"), which is sufficient to effect treatment, as defined in this application when administered to an individual in need of such treatment. In one embodiment, the therapeutically effective amount will be up to 3.5 grams (g) of ezatiostat or a salt thereof administered per day. Preferably, ezatiostat or a salt thereof is administered in an amount of 2 grams per day and more preferably is administered twice a day in equal doses of 1 gram. Such therapeutically effective amount is particularly relevant when the treatment regimen is for 3 weeks of administration of eza-thiostat or a salt thereof followed by one week without administration of the drug. In another embodiment, the therapeutically effective amount will be 3 grams of ezatiostat or a salt thereof administered in a single dose, or 2 equal daily doses of 1.5 grams. Such a therapeutically effective amount is particularly relevant when the treatment regimen is for 30 weeks of administration of ezatiostat or a salt thereof followed by a week without administration of the drug. Preferably, the dosage regimen employs 2 grams of ezatiostat or a salt thereof administered at a dose of 1 gram twice daily under continuous administration or administered for 3 weeks followed by one week without drug administration. .

In one embodiment, the therapeutically effective amount will provide effective results in at least about 10% of the treated population, and preferably at least about 15%.

As used in this application, the term "treating" or "treating" means any treatment of MDS in a patient who produces one or more of the following:

■ inhibition of MDS, ie, suspension or suppression of

experience of clinical symptoms (eg, need for blood transfusion, abnormal blood count and the like); and / or

■ relief from MDS, that is, causing symptom regression.

As used herein, the term "patient" refers to mammals and includes both human and non-human mammals.

2. Methods

In one of its method aspects, this invention is directed to a method for treating a myelodysplastic syndrome (MDS) in a patient in need of the same one in which the patient had prior exposure to lenalidomide, which method comprises said method. treating the patient with ezatiostat or a pharmaceutically acceptable salt thereof.

It was unexpectedly found that patients who were treated with lenalidomide prior to treatment with ezatiosatat hydrochloride exhibited a higher response rate and / or duration when compared to patients who were not pretreated with lenalidomide. For example, as shown in Table 2, the response rate in patients who were not pretreated with lenalidomide is approximately 22% and in patients who were pretreated with lenalidomide the response rate is approximately 30 46%, a more than 100% increase in response rate.

Prior exposure to lenalidomide may be administration of lenalidomide to the patient at any time prior to administration of ezathiostat or a salt thereof. A typical lenalidomide treatment regimen involves a 28-day cycle, during which lenalidomide is administered once a day, each day, for 21 days (3 weeks) followed by a 7-day break (1 week). when no lenalidomide is administered. This 28-day cycle can be repeated for up to 6 months. Lenalidomide capsules have four different strengths: 5 mg, 10 mg, 15 mg and 25 mg.

In some embodiments of this invention, the patient was treated with at least one lenalidomide dosage. In some modalities, 10 the patient was treated with lenalidomide for at least 2 days, 3 days, 4 days, 5 days or 6 days. In some modalities, the patient was treated with lenidomide for at least one week, two weeks, or three weeks. In some modalities, the patient has completed 1, 2, 3, 4, 5, or 6 cycles of lenalidomide treatment. In some embodiments, the patient completed the complete 6-month lenalidomide treatment regimen.

In some embodiments of this invention, the patient being treated with lenalidomide prior to administration of ezatiostat or a salt thereof developed intolerance to lenalidomide and either stopped lenalidomide treatment or switched to a lower lenalidomide dosage prior to administration of ezatiostat or a salt of the same initial. It should be understood that a patient may stop using lenalidomide or switch to a lower lenalidomide dosage after finishing one cycle or during the cycle depending on the patient's tolerance for lenalidomide.

As a thalidomide derivative, lenalidomide can cause many side effects, such as birth defects and other adverse events. Reported adverse events include, but are not limited to, those related to:

• disorders of the blood and lymphatic system such as thrombocytopenia, neutropenia, eg, febrile neutropenia, leukopenia, anemia, haemolytic anemia, eg warm type hemolytic anemia, splenic infarction, bone marrow depression, coagulopathy, hemolysis and refractory anemia; • skin and subcutaneous tissue disorders such as rash, dry skin, bruise, night sweats, increased sweating, bruising and erythema;

• gastrointestinal disorders such as diarrhea, constipation, nausea, abdominal pain, vomiting, upper abdominal pain, dry mouth,

fecal onset, gastrointestinal bleeding, ischemic colitis, intestinal perforation, rectal hemorrhage, colon polyp, diverticulitis, dysphagia, gastritis, gastroenteritis, gastroesophageal reflux disease, irritable bowel syndrome, melena, obstruction pancreatitis biliary, 10 pancreatitis, perirectal abscess, small bowel obstruction, and upper gastrointestinal bleeding;

• respiratory, thoracic and mediastinal disorders such as nasopharyngitis, cough, dyspnea, pharyngitis, epistaxis, exertional dyspnea, rhinitis and bronchitis;

.15 ■ musculoskeletal and connective tissue disorders, such as

arthralgia, back pain, muscle cramp, limb pain, myalgia and peripheral swelling, arthritis, aggravated arthritis, gouty arthritis, neck pain and pyrophosphate chondrocalcinosis;

■ benign or malignant neoplasms, such as acute leukemia, acute myeloid leukemia, bronchoalveolar carcinoma, lung cancer,

foma and prostate cancer;

■ nervous system disorders such as vertigo, headache, hypoesthesia, dysgeusia and peripheral neuropathy;

• infections and infestations such as pneumonia, urinary tract infection, sinusitis, cellulitis, infection, bacteremia, catheter infection, clostridial infection, ear infection, Enterobacter sepsis, fungal infection, virus infection herpes infection, influenza, renal infection, Kleb-siella sepsis, lobar pneumonia, localized infection, oral infection, pseudomonas infection, septic shock, acute sinusitis, sinusitis, Staph-

ylococcus and urosepsis;

■ disorders of metabolism and nutrition such as hypokalemia, anorexia, hypomagnesemia, dehydration, gout, hypernatremia and hypoglycemia;

• psychiatric disorders such as insomnia, confusional state and depression;

■ renal and urinary disorders such as dysuria, renal failure, hematuria, acute renal failure, azotemia, ureteral calculus and mass

renal;

■ disorders of the reproductive system and breast, such as pelvic pain;

• vascular and cardiac disorders such as hypertension, pal-

pitting, congestive heart failure, atrial fibrillation, angina pectoris, cardiac arrest, heart failure, cardiopulmonary arrest, cardiomyopathy, myocardial infarction, myocardial ischemia, aggravated atrial fibrillation, bradycardia, cardiogenic shock, pulmonary edema, supraventricular arrhythmia, tachycardia. arrhythmia and ventricular dysfunction;

.15 · endocrine disorders such as acquired hypothyroidism;

• ear and maze disorders such as dizziness;

• hepatobiliary disorders, such as hyperbilirubinemia, acute cholecystitis, cholecystitis and liver failure;

• endocrine disorders, such as Basedow's disease;

■ immune system disorders such as hypersensitivity;

• general disorders such as disease progression, fall, abnormal angiography, intermittent pyrexia, lump, rigors, and sudden death;

■ administration site conditions such as femoral fracture, transfusion reaction, cervical vertebral fracture, femoral neck fracture,

fractured pelvis, hip fracture, overdose, post-procedure hemorrhage, rib fracture, traffic accident, and spinal compression fracture; and

• other observations, such as increased blood creatinine, reduced hemoglobin, abnormalities of function tests

increase in alanine aminotransferase and increased troponin I.

Most common and / or severe adverse events include neutropenia, thrombocytopenia, pneumonia, rash, anemia, leukopenia, fever, dyspnea, back pain, febrile neutropenia, nausea, diarrhea, pyrexia, sepsis, vertigo, granulocytopenia, chest pain , pulmonary embolism, respiratory distress, pruritus, pancytopenia, muscle cramp, respiratory tract infection, upper respiratory tract infection, asthenia, multiple organ failure, epistaxis, hypoxia, pleural effusion, pneumonitis, pulmonary hypertension, vomiting , increased sweating, arthralgia, limb pain, headache and syncope.

In certain patient populations, one or more of the adverse events are so severe that lenalidomide can no longer be administered to the patient or lenalidomide must be administered in a reduced dosage. In such circumstances, switching from lenalidomide to ezatiostat or a salt thereof or adding ezatiostat or a salt thereof not only avoids the adverse effect but may also provide better therapeutic effect. 15 for ezatiostat or a salt thereof.

In some embodiments of this invention, the patient who is treated with lenalidomide prior to administration of ezatiostat or a salt thereof does not respond to lenalidomide or the response to lenalidomide does not continue continuous treatment with lenalidomide. Approximately 20% of patients administered lenalidomide are reported to have a clinically recognizable response. In such circumstances, treatment of patients who did not respond or failed to respond to lenalidomide with ezatiostat hydrochloride results in an unexpected better therapeutic effect and reduction of clinical symptoms. In this case, treatment with yenalido-mida may continue with administration of ezathostat or a salt thereof at the same or a reduced dosage, or treatment with lenidomide may be completely stopped.

In some embodiments, ezatiostat or a pharmaceutically acceptable salt thereof is administered daily for at least two weeks. In some embodiments, ezatiostat or a pharmaceutically acceptable salt thereof is administered daily for at least three weeks. In other aspects of the method, this invention provides a method for treating a myelodysplastic syndrome (MDS) in a patient, which method comprises concurrently administering lenalidomide to said patient and ezatiostat or a pharmaceutically acceptable salt thereof. In some embodiments, ezatiostat or a pharmaceutically acceptable salt thereof is administered daily for at least two weeks. In some embodiments, ezatiostat or a pharmaceutically acceptable salt thereof is administered daily for at least three weeks. In these cases, the patient may or may not have been treated with lenalidomide 10 prior to administration of ezatiostat hydrochloride. The foregoing includes situations described above.

When administered concurrently, lenalidomide and ezatostatat or a salt thereof may be administered in any manner in which the pharmacological effects of both are manifest in the patient at the same time. Accordingly, concurrent administration of lenalidomide and ezatiostat or a pharmaceutically acceptable salt thereof does not require that a single pharmaceutical composition, the same dosage form, the same route of administration be used for both agents, both agents being administered to the same time or both agents being administered for a similar duration. When administered by the same dosage form and the same route of administration at substantially the same time, they may continue to deliver both active ingredients simultaneously in a novel single pharmaceutical composition according to the present invention. It is understood that in addition to the above, this invention contemplates that a simultaneous administration may be administration of a first and second pharmaceutical composition comprising lenalidide and ezatiostat or a pharmaceutically acceptable salt thereof, respectively. The term "concurrent" includes both simultaneous delivery as well as sequential delivery wherein each drug is administered separately in a manner that provides serum levels of both drugs to the patient at the same time.

As noted above, a clinician employing lenalidomide alone in a patient for MDS treatment at a point in that treatment regimen may add ezathostat or a pharmaceutically acceptable salt thereof as an additional component to treat that patient. Such further addition of ezathostat or a pharmaceutically acceptable salt thereof in combination with lenalidomide constitutes simultaneous administration for the purposes of this invention since the effects of both will be manifest on the patient at the same time.

In another embodiment, this invention is a method of treating MDS by administering ezatiostat or a salt thereof and ialalide followed by administering ezatiostat or a salt thereof alone.

In some embodiments of this invention, when concurrently administered with ezatiostat or a pharmaceutically acceptable salt thereof, lenalidomide is administered in the typical 28-day cycle as described above and may be provided in either dosage strength. In some embodiments, lenalidomide is administered at a reduced dosage and / or frequency, for example, lenalidomide may be administered once every other day, once every 3, 4, 5 or 6 days. Either it may be administered once a week or it may be discontinued while treatment with ezatiostat or a pharmaceutically acceptable salt thereof continues.

Typically, ezatiostat or a salt thereof is administered in a therapeutically effective amount. In some embodiments, ezatostat or a salt thereof is administered by a dosage regimen described in U.S. Patent Application No. 13 / 108,752, entitled "COMPOSITIONS AND METHODS FOR TREATMENT OF MYELODISPLASTIC SYNDROME," filed May 16, 2011 , which is incorporated by reference in its entirety.

In some embodiments, ezatiostat or a salt thereof is administered up to approximately 3.5 grams per day of ezatiostat hydrochloride, or equivalent amount (in terms of ezatiostat content) of ezatiostat itself or another ezatiostat salt. In a preferred embodiment, the dosage of ezatiostat or a salt thereof is a therapeutically effective amount of up to approximately 1.5 grams administered twice daily (b.i.d.).

In one embodiment of this invention, ezatiostat or a salt thereof is administered at dosages of 1 gram twice daily for three weeks followed by a one week break where ezatiostat or a salt thereof is not administered. After discontinuation, the regimen may be repeated as needed. This scheme may be referred to as the "three week regime".

In one embodiment of this invention, ezatiostat or a salt of the

It is administered at dosages of 1.5 grams twice a day for two weeks followed by a one week break where ezatiosat or a salt thereof is not administered. After interruption, the regimen can be repeated as needed. This regime may be referred to as the "two week regime".

In another embodiment of this invention, the patient is continuously treated with a therapeutically effective amount of ezatiostat or a salt thereof of up to 3 grams per day preferably administered in dosages of up to 1.5 grams twice daily. In this embodiment, ezatiosat or a salt thereof may be administered as long as the patient is in need and can tolerate such treatment. It is contemplated that in this embodiment, the therapeutically effective amount of ezatiostat or a salt thereof may be less or more than that when there is an interruption in the treatment regimen. This scheme may be referred to as the "continuous scheme".

Although twice daily administration is preferred, it is contemplated that once daily administration or 3 times daily administration may be employed. In the preceding case, once-daily administration would assist in patient compliance; whereas ultimately 30 smaller tablets can be used for those patients who have difficulty swallowing larger tablets. The amount of drug administered would be adjusted so that the total drug administered per day is a therapeutically effective amount.

Treatment with ezatiostat or a salt thereof may involve one or a combination of two or more of the dosage regimens described in this application. The following are dosage schemes for exemplifying ezatiostat hydrochloride:

• 1.5 grams of ezatiostat hydrochloride administered twice daily for 2 weeks of a total aggregate dosage of 42 grams followed by one week when no ezatiostat or salt is administered;

-1 gram of ezatiostat hydrochloride administered twice

per day for 3 weeks of a total aggregate dosage of 42 grams followed by one week when no ezatiostat or salt is administered;

■ 1 gram of ezatiostat hydrochloride administered twice daily continuously until the attending physician considers the patient appropriate.

, 15 being withdrawn from administration;

■ a therapeutically effective amount of up to 3 grams of ezatiostat hydrochloride per day administered in one, two or three doses divided over 2 weeks followed by one week when no ezatostat or salt is administered;

■ a therapeutically effective amount of up to 2 grams of

ezatiostat hydrochloride per day administered in one, two or three doses divided over 3 weeks followed by one week when no ezatostat or salt is administered; and / or

■ a therapeutically effective amount of up to 2 grams of

ezatiostat hydrochloride administered daily in one, two or three doses

divided continuously until the attending physician considers it appropriate for the patient to be withdrawn from administration.

Ezatiostat hydrochloride in the above dosages may be substituted

by an equivalent amount of ezatiostat itself or another ezatiostat salt (in terms of ezatiostat content).

When administration of ezatiostat or a salt thereof is twice daily, it is preferred that the interval between the first and second dose is approximately 6 to 14 hours and preferably between approximately 8 and 14 hours.

In one embodiment, ezatiostat or a salt thereof, for example ezatiostat hydrochloride, may be administered intravenously as a lipid formulation, such as those described in U.S. Patent No. 7,029,695 which is incorporated by reference in its entirety.

In another embodiment, ezatiostat or a salt thereof, for example ezatiostat hydrochloride, may be administered orally. In one embodiment, ezatiostat or a salt thereof, for example ezatiostat hydrochloride, may be administered as a tablet formulation. Such a tablet formulation is described in US Patent Application No. 13 / 075,116, filed March 29, 2011, entitled "EZATIOSTAT TABLET FORMULATION," which is incorporated by reference .15 in its entirety.

3. Composition

In another aspect, this invention provides a composition comprising lenalidomide and ezatiostat or a pharmaceutically acceptable salt thereof.

In some embodiments, ezatiostat or salt thereof

lidomide together are in a therapeutically effective amount.

In some embodiments, lenalidomide and / or ezatiostat or a salt thereof is in a therapeutically effective amount. In some embodiments, the composition comprises approximately 5 mg, 10 25 mg, 15 mg or 25 mg lenalidomide and approximately 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg of ezatiosat or salt thereof.

In one embodiment, lenalidomide may be added to a lipid formulation of ezatiostat or salt thereof described in U.S. Patent No. 7,029,695.

In another embodiment, lenalidomide may be added to an ezatiostat tablet formulation or a salt thereof. Such a tablet formulation is described in US Patent Application No. 13 / 075,116, filed March 29, 2011, entitled "EZATIOSTAT TABLET FORMULATION," which is incorporated by reference in its entirety.

4. Set

In yet another aspect, this invention provides a kit for treating MDS comprising a first composition comprising lenalidomide and a second composition comprising ezatiostat or a salt thereof, including those described in this application.

In some embodiments, ezatiostat or salt thereof

lidomide together are in a therapeutically effective amount.

In some embodiments, the kit further comprises a label with instructions for administration of the first dose of lenalidomide 1 day, 2 days, 3 days, 4 days, 5 days, 6 days prior to the first administration of .15 ezatiostat or a salt of the same. In some embodiments, the kit further comprises a label with instructions for administration of lenalidomide 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks or 6 weeks prior to administration of ezatiostat or a salt thereof. In some embodiments, the kit further comprises a label with instructions for administration of lenalidomide concurrently with ezatiostat or a salt thereof. In some embodiments, the kit further comprises a label with instructions for administration of lenalidomide and ezatiostat or a salt thereof according to any of the dosage schedules described in this application.

Examples

The present invention is further defined with reference to the following examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the present invention.

Ezatiostat hydrochloride tablets in patients with a low International Prognostic System Score (IPSS) for intermediate risk 1 of myelodysplastic syndrome Eighty-seven patients were randomized and treated at 23 investigational sites. After initial dose ranging in 14 patients, two dose levels were selected for further study. Subsequently, 37 patients were treated with 3 grams daily for two weeks followed by a remaining period of one week, and 36 patients were treated with 2 grams daily for three weeks followed by a remaining period of one week. Data on these 73 patients were pooled for this preliminary analysis.

The median age was 72 years, with a demographic distribution of 10 low-risk IPSS patients (23 patients, 32%) and intermediate risk 1 (50 patients, 68%). Patients had received an average of three prior MDS therapies including, 34 patients (47%) with previous Revlimid® (lenalidomide) and 28 patients (38%) with prior DNA methyl transferase (DMTI) inhibitors [azacitidine, decitabine ],

.15 At the time of the preliminary analysis, 8 patients remained

treatment for continued clinical benefit. The total Erythroid Hematologic Improvement (HI-E) rate was 22%, 13 of 60 evaluable patients (95% CI, 12.1 to 34.2). The median duration of the Hl-E response was 46 weeks (range 2 to 51). The median hemoglobin level increased by 2.0 grams / dL in respondents. Eleven of 38 red blood cell (RBC) transfusion-dependent patients (29%) had clinically significant RBC transfusion reductions (4U / 8 week reduction, IWG 2006) with

4 patients (11%) achieving independence of CBR transfusion and 3 patients continuing treatment. One patient continued complete remission for more than 12 months after discontinuation of therapy (Quddus et al., J. Hem.and One. Apr. 2010, 3:15).

Telintra® continues to demonstrate multilanguage hematological improvement. There was a Hematological - Neutrophil Improvement rate of 15% (Hl-N) observed in 3 of 20 patients (95% CI, 3.2 to 37.9), and the Hl bilinear rate (Hl-E and Hl). -N) was 11%, 2 of 19 patients (95% CI, 1.3 to 33.1).

There were three complete cytogenetic responses, one in a patient with abnormal cytogenetics 45X, -Y [4], 46, XY [16] that converted to normal after four cycles of therapy. Of the four patients enrolled in the 5q minus study, two had a complete cytogenetic response, including one who had failed previous Revlimid® therapy.

A planned logistic regression analysis was used to assess all known prognostic characteristics in order to define those patients who had an increased likelihood of Hin-E response to Telintra®. Prior treatment with DMTI predicts a fivefold reduction in probability for an Hl-E response to Telintra® (p = 0.023). Previous treatment with Revlimid® was found to increase the response of

Hl-E to Telintra®

■ There was a 40% rate of Hl-E (6 of 15 patients, 95% CI, 16.3% to 67.7%) in patients who had previously treated Revlimid® but no prior treatment with DMTI. . Within this patient group, five of 11 patients (45%) achieved transfusion reduction

.15 significant RBC with three of those patients (27%) achieving transfusion independence.

■ There was a 26% Hl-E rate (6 of 23 patients, 95% CI, 10.2% to 48.4%) in patients who had no previous Revlimid® treatment and no previous treatment with Revlimid®. DMTI. Within this

In this group, five of 11 patients (45%) achieved significant CBR transfusion reduction.

• There was a 0% Hl-E rate (0 out of 17 patients, 95% CI, 0% to 19.5%) in patients who had not been previously treated with Revlimid® but had previously received treatment with DMTI.

More than 403 cycles of Telintra® therapy were administered.

Safety data are based on all treated patients. The most common non-haematological adverse events (AEs) were gastrointestinal events Class 1 and 2 (GI) respectively, nausea (45%, 16%), diarrhea (25%, 7%) and vomiting (30%, 12%). Class 3 events were rare:

nausea (1%), diarrhea (3%) and vomiting (2%). Prior treatment with DMTI was associated with an increased incidence of Gl AEs.

Telintra® treatment may result in clinically significant haematological improvement in MDS patients and may offer an alternative to RBC transfusions. These results are consistent with levels of efficacy observed in previous studies with Telintra®, the first GST P1-1 enzyme inhibitor tested in MDS patients.

Tables 1 and 2 summarize the results of this clinical study.

As shown in table 2, increased response rate to Telintra® from approximately 22.2% of patients who had no previous Revlimid® treatment to approximately 46.2% in patients who had Revlimid® treatment prior to Telintra administration. ®.

Table 1

Hematologic Improvement - Erythroid (Hl-E): Response Time and Initial Response Duration of Telintra® Dose of 3,000 mg / day (1.5 g b.i.d.) or 2,000 mg / day (1 g b.i.d.)

(Population with Evaluable Effectiveness)

Telintra® Dosing Scheme 1.5 g b.i.d. 2 weeks yes 1 g b.i.d. 3 weeks yes & 1 week no & 1 week no (N = 29) (N = 31) Response Time Hl-E (Weeks) [1] N 7 6 Average 8.4 (0.72) 8.9 (1 , 29) Median 8.1 8.4 Min, Max 8.0, 10.0 8.0 8.11.3 Response Duration Hl-E (Weeks) [2] # Event 5 (71.4%) 2 ( 33.3%) # Censored 2 (28.6%) 4 (66.7%) Median (95% CI) 18.4 (3.1-51.0) 46.1 (10.0-46.1 ) Min, Max 1.9-51.0 2.4-46.1 [1] Days from date of first dose of medication study to date of first response record plus one divided by 7.

[2] Total number of days from when the answer is viewed divided by 7. Table 2

Hematologic Improvement - Erythroid (HI-E)

(Population with evaluable effectiveness)

Statistics Hl-E [3] Revlimid® N Response Response Rate (n) (Confidence Interval 95%) Yes 13 6 46.2% (19.2% - 74.9%) No 27 6 22.2% ( 8.6% - 42.3%) [3] RBC transfusion reduction from baseline => 4 units for eight weeks; or patient with symptomatic non-transfusion-dependent anemia with hemoglobin <11 g / dL before treatment, achieving an increase in hemoglobin> = 1.5 g / dL maintained for an eight-week period.

Claims (22)

1. Use of ezatiostat or a salt thereof for the preparation of a medicament for the treatment of a myelodysplastic syndrome in a patient who has prior exposure to lenalidomide, where ezatiostat or its salt is administered daily for at least 2 weeks. Use according to claim 1, wherein the patient has developed lenalidomide intolerance. Use according to claim 1, wherein the patient experiences a reduced or absent therapeutic effect with continuous lenalidomide treatment. Use according to any one of claims 1 to 3, wherein the ezatiostat or salt thereof is administered in a therapeutically effective amount. 5. Use of ezatiostat or a salt thereof for the preparation of a medicament for treating a myelodysplastic syndrome in a patient, wherein ezatiostat or a salt thereof is administered with lenidomide. Use according to claim 5, wherein the ezatiostat or salt thereof and lenalidomide are administered together in a therapeutically effective amount. Use according to any one of claims 1 to 6, wherein the ezatiostat or salt thereof is administered orally. The use of claim 7, wherein the ezatiostat or salt thereof is administered according to a treatment schedule comprising administering a daily dosage of 2 grams for three weeks followed by a one week break in no ezatiostat or salt thereof is administered. Use according to claim 7, wherein the ezatiostat or salt thereof is administered according to an administration comprising treatment schedule of a daily dosage of 3 grams for two weeks followed by a one week break in that no ezatiostat or salt thereof is administered. A composition comprising ezathostat or a salt thereof and lenalidomide, and optionally a pharmaceutically acceptable excipient. The composition of claim 10, wherein the ezatiostat or salt thereof and lenalidomide together are in a therapeutically effective amount. An assembly for treating MDS comprising a first composition comprising lenalidomide and a second composition comprising ezatiostat or a salt thereof. An assembly according to claim 12, wherein the ezatostatat or salt thereof and lenalidomide together are in a therapeutically effective amount. A method for treating a myelodysplastic syndrome in a patient who has prior exposure to lenalidomide, which method comprises treating the patient with a therapeutically effective amount of ezatiostat or a salt thereof, wherein ezatiostat or the salt of the It is administered daily for at least 2 weeks. The method of claim 14, wherein the patient has developed lenalidomide intolerance. The method of claim 14, wherein the patient experiences a reduced or absent therapeutic effect with continuous lenalidomide treatment. A method according to any one of claims 14 to 16, wherein the ezatiostat or salt thereof is administered in a therapeutically effective amount. A method for treating a myelodysplastic syndrome in a patient, which method comprises administering to the patient ezathostat or a salt thereof and lenalidomide. The method according to claim 18, wherein the ezatostat or salt thereof and lenalidomide are administered together in a therapeutically effective amount. A method according to any one of claims 14 to 19, wherein the ezatiostat or salt thereof is administered orally. The method of claim 20, wherein the ezatostat or salt thereof is administered according to a treatment schedule comprising administering a daily dosage of 2 grams for three weeks followed by an interruption of a week no ezatiostat or salt is administered. A method according to claim 20, wherein the ezatostat or salt thereof is administered according to an administration comprising treatment schedule of a daily dosage of 3 grams for two weeks followed by a discontinuation of a week no ezatiostat or salt is administered.